The objective of this proposal is to characterize mechanism by which keratinocytes (KC) cooperate with gamma delta T cells to form an immunological defense at the environmental interface. Working hypotheses are that: 1) KC and resident gamma delta T cells play critical roles in maintaining the immunological integrity of skin, 2) certain functions of KC and gamma delta T cells are regulated by locally produced cytokines, and 3) environmental stimuli disrupt this equilibrium by altering these cytokine profiles. Dendritic Epidermal T Cells (DETC), one member of the family of resident epithelial gamma delta T cells in mice, will be studied as a prototypic cutaneous gamma delta T cell. IL-7 and transforming growth factor-Beta (TGFBeta) will be studied as cytokines produced by KC that regulate T cell function, and gamma-interferon (gammaIFN) will be studied as a cytokine produced by T cells that modulates KC function. These hypotheses are derived from observations that: 1) DETC growth is promoted by IL-7 and inhibited by TGFbeta, 2) external stimuli modulate cytokine production in KC (e.g., UVB-induced downregulation of IL-7 MRNA expression and gamma IFN-induced expression of a truncated (2.6 kb) IL-7 transcript, 3) DETC kill skin tumor targets and downregulated alpha/beta T cell-mediate immunity, and 4) gamma delta T cells infiltrate and play effector roles in several human skin disorders. Specific aims are: 1) To determine the physiological roles of IL-7 and TGFbeta in modulating DETC function. Local IL-7 and TGFBeta concentrations will be altered experimentally [cytokine or mAb injection, IL-7 transgenic mice] and DETC in test will be examined for maturation during the neonatal period, modulation of their cell densities, and killing activities. 2) To study IL-7 and TGFBeta gene regulation in KC: a) modulation of IL-7 or TGFBeta production in KC by environmental and cytokine stimuli [Northern blotting, bioassays]; and b) roles of early immediate genes in this regulation [antisense nucleotide blocking]. 3) To identify the function of a gammaIFN-inducible 2.6 kb IL-7 transcript [cDNA cloning and sequencing, mammalian cell expression]. 4) To characterize in vivo functions of DETC. DETC densities will be manipulated experimentally and skin response to alpha/Beta T cell- mediated attack will be examined. 5) To define mechanisms for the cytotoxic recognition of skin tumors by DETC: a) the role played by 2 B4, a novel molecule that mediates non-MHC-restricted target recognition, including b) regulation of 2B4 expression. The proposed studies should lead to a better understanding of cytokine networks in epidermis, the biology of cutaneous gamma delta T cells, and the pathophysiology of T cell-mediated and neoplastic skin disorders in humans.